TRANSPORT OF OXYGEN AND CARBON DIOXIDE IN BLOOD

CONTENTS

• INTRODUCTION • OXYGEN CASCADE • OXYGEN DELIVERY DURING

EXERCISE • OXYGEN DELIVERY DURING

CRITICAL ILLNESS • CARBON DIOXIDE TRANSPORT

O2 TRANSPORT

REQUIREMENTS FOR OXYGEN TRANSPORT SYSTEM

Match O2 supply with demand

MOVEMENT OF O2 DOWN CONCENTRATION GRADIENT

OXYGEN CASCADE

•Oxygen moves down the concentration gradient from a relatively high levels in air to that in the cell

•The PO2reaches the lowest level (4-20 mmHg) in the mitochondria

•This decrease in PO2 from air to the mitochondrion is known as the OXYGEN CASCADE

KEY STEPS IN OXYGEN CASCADE

• Uptake in the lungs • Carrying capacity of blood • Delivery to capillaries • Delivery to interstitium • Delivery to individual cells • Cellular use of oxygen

DETERMINANTS OF PaO2

• Inspired O2 concentration & barometric pressure

• Alveolar ventilation • V/Q distribution & matching • O2 diffusion from alveoli to pul capillaries

Oxygen Transport Carried in bld in 2 forms: 1. by red blood cells Bound to Hb 97-98%

2. Dissolved O2 in plasma Bound to Hgb Dissolved

Obeys Henry’s law PO2 x = O2 conc in sol

= Solubility Coefficient (0.003mL/100mL/mmHg at 37C) Low capacity to carry O2

Hemoglobin • Fe porphyrin compound • Normal adult = HbA = 22

• Hb F= 22 • The chains ↑ hb affinity

to O2 • Each gm of Hb can carry

up to 1.34ml of O2, theoretically up to

1.39 ml/gm

Molecular weight of hemoglobin is 64,000

CHEMICAL BINDING OF HEMOGLOBIN & OXYGEN

• Hemoglobin combines reversibly with O2

• Association and dissociation of Hb & O2 occurs within milliseconds – Critically fast reaction important for O2 exchange – Very loose coordination bonds between Fe2+ and O2,

easily reversible

• Oxygen carried in molecular state (O2) not ionic O2-

Oxygen Saturation & Capacity

• Up to four oxygen molecules can bind to one hemoglobin (Hb)

• Ratio of oxygen bound to Hb compared to total amount that can be bound is Oxygen Saturation

• Maximal amount of O2 bound to Hb is defined as the Oxygen Capacity

O2 Content in blood (CaO2)

• 97-98% Carried in Combination With Hb • 2-3% Dissolved in Plasma

O2 CONTENT -The sum of O2 carried on Hb and dissolved in plasma

CaO2 (ml/dL) = (SaO2 x Hb x 1.34) + (PO2 x0.003)

• O2 content in 100 ml blood (in normal adult with Hb 15 gm/dl) ~ 20 ml/dl (19.4 ml as OxyHb + 0.3 ml in plasma)

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50

If the PAO2 is ↑ed significantly (by breathing 100% oxygen) then a small amount of extra oxygen will dissolve in the plasma (at a rate of 0.003 ml O2/100ml of blood /mmHg PO2) but there will normally be no significant increase in the amount carried by haemoglobin

Venous O2 content (CvO2) CvO2 =(SvO2 x Hb x 1.34) + (PvO2 x 0.003) ‒ (normally-15ml/dl)

• mixed venous saturation (SvO2 ) measured in the pul A represents the pooled venous saturation from all organs.

• SvO2 influenced by changes in both DO2 and VO2

• Normally, the SvO2 is about 75%, however, clinically an SvO2 of about 65% is acceptable

Arterial-Venous Difference • The arterial-venous oxygen content difference is

the difference between the CaO2 and the CvO2. • The normal C(a-v)O2 : 5 vol%.

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Factors that increase the C(a-v)O2:

• decreased cardiac output • increased O2consumption • exercise • seizures • shivering • increased temp

Factors that decrease the C(a-v)O2:

• increased cardiac output • skeletal relaxation (drugs) • peripheral shunting • poisons • decreased temp

O2 DELIVERY DO2 (ml/min) = Q x CaO2 x 10

DO2 = Q x Hb x SaO2 x 1.34 x 10 (multiplier of 10 is used to convert CaO2 from ml/dl to ml/L)

N- 900-1,100 ml/min

• Decreased oxygen delivery occurs when there is: – ↓ed cardiac output – ↓ed hemoglobin concentration – ↓ed blood oxygenation

O2 CONSUMPTION • The amount of oxygen extracted by the peripheral tissues

during the period of one minute is called oxygen consumption or VO2. (N- 200-300ml/min)

VO2 = Q x (CaO2 - CvO2) x 10 = Q x 1.34 x Hb x (SaO2-SvO2) x 10

• O2 consumption is commonly indexed by the patients body surface area (BSA) and calculated by: – VO2 / BSA – Normal VO2 index is between 110 – 160ml/min/m2

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OXYGEN EXTRACTION RATIO • The oxygen extraction ratio (O2ER) is the amount of oxygen

extracted by the peripheral tissues divided by the amount of O2 delivered to the peripheral cells.

• Index of efficiency of O2 transport • aka: Oxygen coefficient ratio & Oxygen utilization ratio

– O2ER = VO2 / DO2 – When SaO2 ~1 :

O2ER ~ SaO2-SvO2 – Normally ~ 25% but to 70-80% during maximal

exercise in well trained athletes

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Factors that affect O2ER

•Increased with: •Decreased with: •Decreased CO •Increased Cardiac Output •Increased VO2 •Skeletal Muscle Relaxation

•Exercise •Peripheral Shunting •Seizures •Certain Poisons

.•Shivering •Hypothermia •Hyperthermia •Increased Hemoglobin

•Anemia •Increased PaO2

•Low PaO2

•In general, DO2 >> VO2 •When oxygen consumption is high (exercise) the ↑ed O2 requirement is usually provided by an ↑ed CO

•Alternatively, if oxygen delivery falls relative to oxygen consumption the tissues extract more oxygen from the hb (the saturation of mixed venous blood falls below 70%) (a-b )

CRITICAL DO2

A reduction below point 'c' in figure cannot be compensated for by an increased oxygen extraction and results in anaerobic metabolism and lactic acidosis.

O2 DIFFUSION FROM

INTERSTITIUM TO CELLS Intracellular PO2 < Interstitial fluid PO2 • O2 constantly utilized by the cells • Cellular metabolic rate determines overall O2

consumption

N PcO2 ~ 5-40 mm Hg (average 23 mmHg) N intracellular req for optimal maintenance of

metabolic pathways ~ 3 mm Hg

Pasteur point –

critical mitochondrial PO2 below which aerobic metabolism cannot occur

0.15 – 0.3 kPa = 1.4 – 2.3mmHg

Oxygen Dissociation Curve The relationship between the partial pressure of oxygen and the saturation of oxygen.

OXYGEN DISSOCIATION CURVE

Sigmoid Shaped

The amount of oxygen that is saturated on the hemoglobin (SO2) is dependent on the amount dissolved (PO2).

Amount of O2 carried by Hb rises rapidly upto PO2 of 60mmHg but above that curve becomes flatter

When Hb takes up small amount of O2 – relaxed state favours – additional uptake

Combination Of 1st Heme with O2 increases affinity of 2nd

Heme and so on

Significance of the S-shape curve

100%

Plateau:

► haemoglobin highly saturated with O2

% saturation of favour the loading of O2 in lunghaemoglobin

Steep slope:

partial pressure of O2 (mmHg)

► small drop of O2 partial pressure leads to a rapid decrease in % saturation of haemoglobin

► favour the release of O2 in tissue cells

Steep Portion of Curve

• “Dissociation Portion” of curve. • Between 10 and 60 mm Hg. • Small increases in PO2 yield large increases in

SO2. • At the tissue capillary, blood comes in contact

with reduced tissue PO2 and oxygen diffuses from the capillary to the tissue.

Flat Portion of Curve

• “Association Portion” of curve. • Greater than 60 mm Hg. • Large increases in PO2 yield small increases in SO2. • At the pulmonary capillary, blood comes in contact

with increased alveolar PO2 and oxygen diffuses from the alveolus to the capillary. As the PO2 rises, oxygen binds with the hemoglobin (increasing SO2).

• Very little rise in oxygen saturation above 100 mm Hg of PaO2.

Rules of Thumb of the Oxyhemoglobin Curve

PO2 SO2

27 50

40 75

60 90

250 100

PO2 SO2

40 70

50 80

60 90

P50 • The partial pressure of oxygen in the blood at which

the haemoglobin is 50% saturated, is known as the P50.

• The P50 is a conventional measure of haemoglobin affinity for oxygen

• Normal P50 value is 26.7 mm Hg • As P50 increases/decreases, we say the “curve has

shifted”. – P50 less than 27: Shift to the left. – P50 greater than 27: Shift to the right.

Factors affecting Dissociation BLOOD TEMPERATURE • increased blood temperature • reduces haemoglobin affinity for O2

BLOOD Ph • lowering of blood pH (making blood

more acidic) • caused by presence of H+ ions from

lactic acid or carbonic acid • reduces affinity of Hb for O2

CARBON DIOXIDE CONCENTRATION • the higher CO2 concentration in

tissue • the less the affinity of Hb for O2

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RIGHT SHIFT

LEFT SHIFT

Decreasing P50.

Increasing P50

Bohr Effect

• By Christian Bohr in 1904 • The effect of CO2 on the OHDC is known as

the Bohr Effect • High PCO2 levels and low pH decrease affinity

of hemoglobin for oxygen (a right-ward shift). • This occurs at the tissues where a high level of

PCO2 and acidemia contribute to the unloading of oxygen.

Bohr effect – the effect of [CO2] on haemoglobin

100%

% saturation of haemoglobin

Higher [CO2] e.g. tissue cells

Lower [CO2] ► haemoglobin has a lowere.g. in lung

► curve shift to the left ► haemoglobin has a higher affinity to O2 partial pressure

of O2 (mmHg)

► curve shift to the right

affinity to O2

pH & pO2: BOHR EFFECT

IMPLICATIONS OF BOHR EFECT

• Enhance oxygenation of blood in lungs and to enhance release of O2 in the tissues

• In lungs, CO2 diffuses out of the blood (H+ conc due to in H2CO3 conc) Shift of O2-Hb curve to left O2 bound to Hb O2 transport to tissues.

• In tissue capillaries, CO2 and H+ greater release of O2 due to less avid binding of O2 to Hb.

DOUBLE BOHR EFFECT • Reciprocal changes in acid - base balance that occur in

maternal & fetal blood in transit through the placenta

FETAL BLOOD MATERNAL BLOOD Loss of CO2 Gain of CO2

Rise in pH Fall in pH

Leftward shift of ODC Rightward shift of ODC

Oxygen dissociation curve: Foetal VS Maternal

% saturation of haemoglobin

partial pressure of O2 (mmHg)

→ Foetal haemoglobin has higher affinity to O2 so as obtain O2 from maternal blood in the placenta.

Maternal

Foetal

ROLE OF 2,3 DPG(diphosphoglycerate)

2,3 DPG is an organic phosphate normally found in the RBC Produced during Anaerobic glycolysis in RBCS

2,3 DPG

• Tendency to bind to β chains of Hb and thereby decrease the affinity of Hemoglobin for oxygen.

• HbO2 + 2,3 DPG → Hb-2,3 DPG + O 2

• It promotes a rightward shift and enhances oxygen unloading at the tissues.

• This shift is longer in duration than that due to [H+],PCO2 or temperature.

– A doubling of DPG will result in a 10 torr increase in P50.

2,3 DPG • The levels increase with

– Cellular hypoxia. – Anemia – Hypoxemia secondary to

COPD – Congenital Heart Disease – Ascent to high altitudes

• The levels decrease with

– Septic Shock – Acidemia – Stored blood

• No DPG after 2 weeks of storage.

EFFECTS OF 2,3-BPG ON STORED BLOOD

• In banked blood , the 2,3-BPG level falls and the ability of this blood to release O2 to the tissues is reduced.

• less if blood is stored in citrate–phosphate–dextrose solution than acid–citrate–dextrose solution.

Effects of anemia & CO on the oxyhemoglobin dissociation curve

Anemia • ↓OCC of blood & O2 content; • SaO2 remains normal

Carbon Monoxide [CO] • affinity of Hb for CO is

250 fold relative to O2 competes with O2 binding

• L shift- interfere with O2 unloading at tissues

• severe tissue hypoxia

CHANGE THE SHAPE OF OHDC

• sigmoidal HbO2 curve becomes hyperbolic

Oxygen dissociation curve: Haemoglobin VS Myoglobin

% saturation of haemoglobin

partial pressure of O2 (mmHg)

→ Myoglobin stores O2 in muscles and release it only when the O2 partial pressure is very low.

Haemoglobin

Myoglobin

Myoglobin has an increased affinity for O2

(binds O2 at lower Po2)

O2 DELIVERY DURING EXERCISE

• During strenuous exercise VO2 may to 20 times N

• Blood also remains in the capillary for <1/2 N time due to C.O.

O2 Sat not affected • Blood fully sat in first 1/3 of N time available

to pass through pul circulation

• Diffusion capacity upto 3 fold since:

1.Additional capillaries open up no of capillaries participating in diffusion process

2. Dilatation of both alveoli and capillaries alveolo-capillary distance

3. Improved V/Q ratio in upper part of lungs due to blood flow to upper part of lungs

Shift of O2-Hb dissociation curve to right because of:

1. CO2 released from exercising muscles 2. H+ ions pH 3. Temp 4. Release of phospates 2,3 - DPG

OXYGEN DELIVERY IN CRITICAL ILLNESS

• Tissue hypoxia is due to disordered regional distribution of blood flow

• often caused by capillary microthrombosis after endothelial damage and neutrophil activation rather than by arterial hypoxaemia

OXYGEN STORES

• o2 stores are limited to lung and blood. • The amount of O2 in the lung is dependent on

the FRC and the alveolar concentration of oxygen.

• Breathing 100% oxygen causes a large increase in the total stores as the FRC fills with oxygen

• This is the reason why pre-oxygenation is so effective.

THE EFFECTS OF ANAESTHESIA • The normal protective response to hypoxia is

reduced by anaesthetic drugs and this effect extends into the post-operative period.

• Following induction of anaesthesia : FRC ↓

• V/Q mismatch is ↑ed • Atelectasis develops rapidly • This 'venous admixture' increases from N 1% to around

10% following induction of anaesthesia.

THE EFFECTS OF ANAESTHESIA

• Volatile anaesthetic agents suppress hypoxic pulmonary vasoconstriction.

• Many anaesthetic agents depress CO and therefore ↓ O2 delivery.

• Anaesthesia causes a 15% ↓ in metabolic rate and therefore a reduction in oxygen requirements.

• Artificial ventilation causes a further 6% ↓ in oxygen requirements as the work of breathing is removed.

Pulmonary Shunting • PERFUSION WITHOUT VENTILATION. • Pulmonary shunt is that portion of the cardiac

output that enters the left side of the heart without coming in contact with an alveolus. – “True” Shunt – No contact

• Anatomic shunts (Thebesian, Pleural, Bronchial) • Cardiac anomalies

– “Shunt-Like” (Relative) Shunt • Some ventilation, but not enough to allow for complete

equilibration between alveolar gas and perfusion.

• Shunts are refractory to oxygen therapy.

Venous Admixture • Venous admixture is the mixing of shunted,

non-reoxygenated blood with reoxygenated blood distal to the alveoli

• resulting in a reduction in: – PaO2

– SaO2

• Normal Shunt: 3 to 5% • Shunts above 15% are associated with

significant hypoxemia

CO2 TRANSPORT

INTRODUCTION TO PHSYIOLOGY OF CO2 TRANSPORT

• end-product of aerobic metabolism. – production averages 200 ml/min in resting

adult – During exercise this amount may increase 6x

• Produced almost entirely in the mitochondria. • Importance of co2 elimination lies in the fact

that -Ventilatory control system is more responsive to PaCO2 changes.

• Carbon dioxide is transported in the bloodfrom the tissue to the lungs in 3 ways:

(i) dissolved in solution; (ii) buffered with water as carbonic acid; (iii) bound to proteins, particularly haemoglobin.

• Approximately 75% of carbon dioxide is transport in the red blood cell and 25% in the plasmaattributable to – lack of carbonic anhydrase in plasma – plasma plays little role in buffering and combination

with plasma proteins is poor.

Dissolved carbon dioxide • Carbon dioxide is 20 times more soluble than oxygen; • obeys HENRY’S LAW, which states that the number of

molecules in solution is proportional to the partial pressure at the liquid surface.

PCO2 x = CO2 conc in sol = Solubility Coefficient

Value dependant upon temp (inversely proportional) more temp lesser amount of CO2 dissolved. • The carbon dioxide solubility coefficient is 0.69 ml/L/mm Hg

at 37C.

• At rest, contribution of dissolved CO2 to total A-V CO2 conc diff only 10%. In absolute terms only 0.3 ml of CO2/dL transported in dissolved form

• During heavy exercise contribution of dissolved CO2 can 7 fold 1/3 of total CO2 exchange

CO2 BOUND AS HCO3 •Dissolved CO2 in blood reacts with water to form Carbonic Acid

•CO2 + H2O H2CO3

Carbonic acid dissociates into H+ & HCO3 H2CO3 H + HCO3

When conc of these ions inc in RBCs, HCO3 diffuses out

but H+ can’t easily do this because cell memb is relatively impermeable to cations.

Thus to maintain electrical neutrality, Cl-ions move into cell from plasma [

CHLORIDE SHIFT] Band 3 HCO3/Clcarrier protein in RBC memb

Movement of gases at tissue level

Resp for 70% of CO2 transport

• Most of H+ combine with Hb because reduced Hb is less acidic so better proton acceptor

• This fact that deoxygenation of the blood inc its ability to carry CO2 is known as HALDANE EFFECT.

• As a result of the shift of chloride ions into the red cell and the buffering of hydrogen ions onto reduced haemoglobin, the intercellular osmolarity increases slightly an →→ water enters causing the cell to swel →→ an increase in mean corpuscular volume (MCV)..

• Hematocrit of venous blood is 3%>arterial

• Venous RBC are more fragile

• Cl content of RBCs V>A

CO2 BOUND AS CARBAMATE • 15-25% of total CO2 transport • CO2 reacts directly with terminal amine group of Hb to

form the carbaminoHb (Hgb.CO) • Reversible RX • Amount of CO2 bound as carbamate to Hb or plasma

proteins depends on: 1) O2 Sat of Hb 2) H+ conc

During passage of blood through muscle & tissues, O2 Sat and H+ conc change considerably, in particular during exercise.

Reduction of Hb ( oxygenation of heme)

basicity of HbTISSUES H+ binding to reduced Hb

dissociation of H2CO3

carriage of CO2 as HCO3

Oxygenation of Hb

acidity of Hb

tendency to combine with H+ binding to Hb

CO2 to form Hgb.CO Release of H+ from Hb

Displacement of CO2 from Hb formation of H2CO3

release of CO2

LUNGS

CO2 DISSOCIATION CURVE Carbon dioxide dissociation curves

• Total CO2 carriage in relate PaCO2 to the amount of carbon dioxide carried in bloodthe blood depends on

the three blood-gas

parameters:

– PCO2

– Plasma pH

– PO2

CARBON DIOXIDE DISSOCIATION CURVE

•carbamino hb is much affected by the state of oxygenation of hb, less so by the PCO2. •Lower the saturation of Hb with O2 , larger the CO2 conc for a given PaCO2 •CO2 curve is shifted to right by increase in SpO2

• CO2 content rises throughout the increase in partial pressure.

• O2content rises more steeply until a point at which the hb is fully saturated. After that, the increase is small because of the small increased amount in solution.

• Consequently, the CO2 curve is more linear than the O2Hb dissociation curve.

• Graph illustrates the difference between the content in blood of oxygen and carbon dioxide with change in partial pressure.

THANK YOU

O2 DELIVERY FROM LUNGS TO TISSUES

• Major function of circulation to transport O2 from lungs to peripheral tissues at a rate that satisfies overall oxygen consumption.

Under normal resting conditions -DO2 >> VO2